The discovery of the alpha-helix and beta-sheet, the principal structural features of proteins.

Howard Hughes Medical Institute and University of California-Department of Energy Institute of Genomics and Proteomics, University of California, Los Angeles, CA 90095-1570, USA. david@mbi.ucla.edu

Abstract

PNAS papers by Linus Pauling, Robert Corey, and Herman Branson in the spring of 1951 proposed the alpha-helix and the beta-sheet, now known to form the backbones of tens of thousands of proteins. They deduced these fundamental building blocks from properties of small molecules, known both from crystal structures and from Pauling's resonance theory of chemical bonding that predicted planar peptide groups. Earlier attempts by others to build models for protein helices had failed both by including nonplanar peptides and by insisting on helices with an integral number of units per turn. In major respects, the Pauling-Corey-Branson models were astoundingly correct, including bond lengths that were not surpassed in accuracy for >40 years. However, they did not consider the hand of the helix or the possibility of bent sheets. They also proposed structures and functions that have not been found, including the gamma-helix.

Linus Pauling and Robert Corey (A) and Herman Branson (B). Pauling's deep understanding of chemical structure and bonding, his retentive memory for details, and his creative flair were all factors in in the discovery of the α-helix. Robert Corey was a dignified and shy x-ray crystallographer with the know-how and patience to work out difficult structures, providing Pauling with the fundamental information he needed. Herman Branson was a physicist on leave at the California Institute of Technology, who was directed by Pauling to find all helices consistent with the rules of structural chemistry that he and Corey had determined. The wooden helix between Pauling and Corey has a scale of 1 inch per Å, an enlargement of 254,000,000 times. (A) Courtesy of the Archives, California Institute of Technology. (B) Courtesy of the Lincoln University of Pennsylvania Archives.

The next two paragraphs concisely set out the method: “The problem we have set ourselves is that of finding all hydrogen-bonded structures for a single polypeptide chain, in which the residues are equivalent (except for the differences in the side chain R).” That is, the authors sought all possible repeating structures (helices) in which the carbonyl CO group of each amino acid residue accepts an N—H hydrogen bond from another residue. Why did they believe that there would be only a small number of types of helices? This was because of the constraints on structure imposed by the precise bond lengths bond angles they had found from their past studies of crystal structures of amino acids and peptides, the components from which proteins are built up. These constraints are summarized in the third paragraph of their paper, which specifies to three significant figures the bond lengths and bond angles that they had found. The most important constraint was that all six atoms of the amide (or peptide) group, which joins each amino acid residue to the next in the protein chain, lie in a single plane. Pauling had predicted planar peptide groups because of resonance of electrons between the double bond of the carbonyl group and the amide C—N bond of the peptide group ().

The α-helix (Left) and the γ-helix (Right), as depicted in the 1951 paper by Pauling, Corey, and Branson (). Biochemists will note that the CO groups of the α-helix point in the direction of its C terminus, whereas those of the γ-helix point toward its N terminus, and, further, that the α-helix shown is left-handed and made up of d-amino acids. (Reproduced with permission from Linda Pauling Kamb.)